# Transcriptional Control of T Cell Function

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2022 · $410,000

## Abstract

PROJECT SUMMARY
 T cells responding to cancer develop a hyporesponsive phenotype, characterized by high levels of inhibitory
receptor expression, low cytokine production, and a failure to control tumor growth. We have previously identified
a transcriptional program induced by persistent antigen stimulation that was shared by mouse and human T cells
responding to chronic viral infections and tumors. We linked this program to activation of the Nuclear Receptor
Subfamily 4 Group A (NR4A) transcription factors (TFs), which are potently induced during chronic stimulation.
We also identified NR4A-sensitive regulatory elements that became accessible in T cells responding to chronic
viral infection and tumors. We found that NR4A TFs concomitantly promoted inhibitory receptor expression and
limited cytokine production, leading to an exhausted T cell state that reduced chimeric antigen receptor
expressing T (CAR-T) cell activity against solid tumors. CAR-T cells engineered to lack all three NR4A TFs
differentiated to a unique population with potent anti-tumor activity compared to wild-type T cells. We connected
this improved function to increased expression and activity of basic leucine zipper (bZIP) TFs in NR4A-deficient
T cells than in wild-type. In new preliminary studies, we found that CAR-T cells with a partial loss of NR4A TFs
also provided better protection than wild-type CAR-T cells, but had a unique “exhaustion resistant” phenotype
that are poised for effector function and have increased potential for long term survival. In this application, we
will test the hypothesis that NR4A and bZIP TFs can be “tuned” to control the transcriptional programs and
function of “exhaustion resistant” CAR-T cells in tumors. In Aim 1, we will determine the impact of therapeutic
interventions, using antibodies or small molecules, on the function and survival of “exhaustion resistant” CAR-T
cells. In Aim 2, we will determine the contribution of NR4A regulated bZIP TFs to the function of NR4A-deficient
CAR-T cells and their effects on transcriptional programs in “exhaustion resistant” CAR-T cells. In Aim 3, we will
define the effects of NR4A TFs on bZIP TF activity at regulatory elements and identify chromatin associated co-
factors that may be targeted to control the function of “exhaustion resistant” CAR-T cells. The expected outcome
of our proposed studies is a comprehensive understanding of the effects of NR4A and bZIP TFs on CAR-T cells
in tumors, through which we will identify practical strategies to “tune” the function of CAR-T cells for therapeutic
benefit by controlling transcriptional programs.

## Key facts

- **NIH application ID:** 10376261
- **Project number:** 5R01AI151021-02
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** JAMES SCOTT-BROWNE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2021-03-22 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376261

## Citation

> US National Institutes of Health, RePORTER application 10376261, Transcriptional Control of T Cell Function (5R01AI151021-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10376261. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*